Effective interventions for osteoarthritis (OA) are limited, and innovative research approaches are needed to advance the detection, prevention, and treatment of this common and disabling disease. Injury-mediated OA provides a unique model of OA, one in which the onset of joint metabolism changes can be clearly identified (the time of injury) and where progression to OA is faster than via non-injury pathways. Abnormal human movement biomechanics and biochemical marker levels may be critical identifiers of individuals at high risk for injury-mediated OA who would benefit from interventions such as neuromuscular training programs preor post-injury. We have the remarkable opportunity to examine the course of OA among large existing cohort with Anterior Cruciate Ligament (ACL) injury. The proposed study will advance our understanding of key markers (biochemical and biomechanical) associated with OA and ofthe role of injury in accelerafing the onset of OA. This proposal benefits from: 1) existing serum samples and epidemiological, injury, and biomechanical data from a large cohort of young military cadets, and 2) well-established collaborations between prolific epidemiologic, biomechanics, biomarker, and osteoarthritis investigators. Specific Aims of the project are: 1) Determine whether serum biomarkers of joint metabolism are associated cross-sectionally with movement biomechanics in subjects with no ACL injury; 2) Determine longitudinally whether serum biomarkers of joint metabolism are altered following incident ACL injury, relative to pre-injury levels in the same subjects, and in comparison to non-injured participants; 3) Quantify the increase in the risk of radiographic ipsilateral knee OA following incident ACL injury; 4) Determine whether longitudinal changes in serum biomarkers associated with ACL injury predict risk of ipsilateral knee OA (in subjects with incident ACL injury). This study is timely, innovative, cost-efficient, and of great signficance in the quest to understand mechanisms underiying the development of OA in response to joint injury.